Integrins are a class of cellular receptors known to bind extracellular matrix proteins, and therefore mediate cell-cell and cell-extracellular matrix interactions, referred generally to as adhäsion events. Integrins receptors constitute a family of proteins across membranes with shared structural characteristics heterodimeric glycoprotein complexes formed of α and β subunits.
One class of integrin receptors, the vitronectin receptor, named for its original characteristic of preferential binding to vitronectin, is known to refer to three different integrins, designated. αvβ1, αvβ3 and/or αvβ5. Horton, Int. J. Exp. Pathol., 71:741-759 (1990). αvβ1 binds fibronectin and vitronectin. αvβ3 binds a large variety of ligands, including fibrin, fibrinogen, laminin, thrombospondin, vitronectin, von Willebrand's factor, osteospontin and bone sialoprotein I. αvβ5 binds vitronectin. The specific cell adhesion roles these three integrins play in the many cellular interactions in tissues is still under investigation, but it is clear that there are different integrins with different biological functions.
One important recognition site in the ligand for many integrins is the arginine-glycine-aspartic acid (RGD) tripeptide sequence. RGD is found in all of the ligands identified above for the vitronectin receptor integrins. This RGD recognition site can be mimicked by polypeptides (“peptides”) that contain the RGD sequence, and such RGD peptides are known inhibitors of integrin function.
Integrin inhibitors containing the RGD sequence are disclosed, for example, in EP 0 770 622 A2. The compounds described inhibit in particular the interactions of β3- and/or β5-integrin receptors with ligands and are particularly active in the case of the integrins αvβ3, αvβ5 and aIIβ3, but also relative to αvβ1, αvβ6 and αvβ8 receptors. These actions can be demonstrated, for example, according to the method described by J. W. Smith et al. in J. Biol. Chem. 265, 12267-12271 (1990). In addition, the compounds possess anti-inflammatory effects.
On basis of integrin inhibitors containing the RGD sequence a multitude of antagonists without the RGD sequence have been made available. Those integrin inhibitors without RGD sequence are disclosed, for example, in WO 96/00730 A1, WO 96/18602 A1, WO 97/37655 A1, WO 97/06791 A1, WO 97/45137 A1, WO 97/23451 A1, WO 97/23480 A1, WO 97/44333 A1, WO 98/00395 A1, WO 98/14192 A1, WO 98/30542 A1, WO 99/11626 A1, WO 99/15178 A1, WO 99/15508 A1, WO 99/26945 A1, WO 99/44994 A1, WO 99/45927 A1, WO 99/50249 A2, WO 00/03973 A1, WO 00/09143 A1, WO 00/09503 A1, WO 00/33838 A1.
DE 1970540 A1 disclose bicyclic aromatic amino acids acting as integrin inhibitors of the αv integrin receptors, particulary of the integrins αvβ3 and αvβ5. The compounds are very particularly active as adhesion receptor antagonists for the vitronectin receptor αvβ3. This effect can be demonstrated, for example, by the method described by J. W. Smith et al. in J. Biol. Chem. 265, 11008-11013 and 12267-12271 (1990).
WO 00/26212 A1 discloses chromenone and chromanone derivatives acting as integrin inhibitors of the αv integrin receptors, particulary of the integrins αvβ3 and αvβ5. The compounds are also very particularly active as adhesion receptor antagonists for the vitronectin receptor αvβ3.
Integrin inhibitors have been suggested as pharmaceutically active principle in human and veterinary medicine, in particular for the prophylaxis and treatment of various disorders. Specifically suggested have been their use for the treatment and prophylaxis of the circulation, thrombosis, cardiac infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, tumor disorders, osteolytic disorders, especially osteoporosis, angiogenesis and disorders resulting from angiogenesis, for example diabetic retinopathy of the eye, macular degeneration, myopia, ocular histoplasmosis, rheumatic arthritis, osteoarthritis, rubeotic glaucoma, and also ulcerative colitis, Crohn's disease, multiple sclerosis, psoriasis and restenosis following angioplasty.
Eye diseases resulting from angiogenesis are the leading cause of visual loss in America. While in case of the population of the age of over 65 visual loss is predominantly effected by age-related macular degeneration (AMD) in case of population of the age of less than 65 this is predominantly effected by diabetic retinopathy.
In Wall Street Journal from Mar. 6 th, 2000 an overview about occurence and current therapies of AMD is given. According to this AMD currently afflicts some 12 million Americans. AMD progressively destroys the macula which is responsible for central vision and color vision. In some cases, deterioration of central vision to fuzzy blur can be rapid occuring in weeks or months. Two forms of the disease exists called “atrophic” and “exudative”. Although exudative AMD effects only 10% of the total AMD population, it accounts for 90% of all AMD-related blindness.
Until recently, the only treatment for exudative AMD consisted of directing a powerful laser beam at the harmful blood vessels to heat and coagulate them. However, only about 15% of patients with exudative AMD have been eligible for this laser surgery. Other therapies are currently in experimental phase. In one approach, called photodynamic therapy, a low-power laser is combined with injection of light-absorbing dye. Another therapy is a more surgical approach and is called “limited retinal translocation”. In this therapy the leaky vessels are destroyed with a high-powered laser after separation and rotation of the retina from the outer wall of the eye.
U.S. Pat. No. 5,766,591 discribes the use of RGD-containing αvβ3 antagonists for the treatment of patients in which neovascularisation in the retinal tissue occurs. More specifically the use of said antagonists for the treatment of patients with diabetic retinopathy, macular degeneration and neovasular glaucoma is suggested. However, no examples with regard to this indications are presented. Concerning to the route of administration only general information are given. Specifically intravenous, intraperitoneal, intramuscular, intracavital and transdermal application is mentioned. In all cases αvβ3 antagonists are preferred exhibiting selectivity for αvβ3 over other integrins such as αvβ5.
WO 97/06791 A1 discribes that αvβ5 antagonists can be used for inhibiting angiogenesis too. Likewise as suggested for αvβ3 antagonists in U.S. Pat. No. 5,766,591 αvβ5 antagonists are suggested for the treatment of a patient with diabetic retinopathy, macular degeneration and neovasular glaucoma. With regard to the route of administration intravenous, intraocular, intrasynovial, intramuscular, transdermal and oral application is specifically mentioned.
WO 00/07565 A1 discribes a method for application of pharmaceutically active substances to the eye via intrascleral injection into the scleral layer. The whole disclosure of WO 00/07565 A1 is incorporated to the present application by reference. As active substances a multitude of active substances is mentioned in WO 00/07565 A1 including integrin blockers. However, the term integrin blocker is silent with regard to the receptor type and refer to all substances acting as inhibitor on anyone of the large class of heterodimeric receptors formed from α and β subunits. Moreover, no examples for integrin blockers are given.